Influenza viruses infect humans and animals and have incurred great financial and societal cost for decades. The most common flu viruses infecting humans are the type A and type B viruses. Influenza A viruses are responsible for sporadic pandemics that usually cause higher mortality rates than seasonal influenza epidemics. The most severe pandemic (“the Spanish flu”) occurred in 1918, with approximately 50 million deaths worldwide (1% of the world's population, 2.5% case:fatality rate). Most recently, the serious threat posed by influenza viruses to worldwide public health has been highlighted by, (i) firstly, the transmission to humans of the highly pathogenic avian influenza A viruses such as the recurrent H5N1 (53% mortality in infected humans; WHO/GIP data in HQ as of 9 May 2016, http://www.who.int/influenza/human_animal_interface/EN_GIP_220160509cumulativenumberH 5N1cases.pdf?ua=1), H7N9 (2 waves in China in 2013 and 2014 with high rates of severe illness and death) and H10N8 (first case reported in China in 2013), and (ii) secondly, the unexpected emergence in 2009 of a novel pandemic influenza virus strain, the swineA/H1N1, that has rapidly spread around the world (http://www.who.int/csr/disease/swineflu/en/). Fortunately, these strains were respectively highly pathogenic but poorly human-to-human transmissible, and highly transmissible but causing only mild illness. A catastrophic, yet plausible, scenario would be the generation by genetic mutation(s) of strains highly pathogenic and contagious and requires constant monitoring.
Besides pandemics, seasonal epidemics occur mainly during the winter months in temperate climates or throughout the year in tropical regions. WHO estimates that annual epidemics cause 3 to 5 million cases of severe illness and 250,000-500,000 deaths worldwide per year (http://www.who.int/mediacentre/factsheets/fs211/en/). Hospitalization and death occur mainly in high-risk populations, the very young, elderly, chronically ill, pregnant woman and immunocompromised patients. On the general population, flu epidemics can result in substantial absenteeism and productivity losses.
Convential prophylactic and therapeutic treatments are the seasonal vaccine and direct acting antivirals. The vaccine is, however, poorly effective in the elderly and children under the age of two, and some years poorly or totally ineffective due to failed prediction of the epidemic strains. Also, it should be noted that the delay in generating a vaccine (˜6 months in the relatively favorable case of A/H1N1) and the lack of vaccinal coverage against highly pathogenic strains highlight the need for therapeutic options.
Two classes of licenced pathogen-targeting antivirals exist: the M2 ion channel blockers (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir). They respectively block the virus life cycle at the entry and release stages. The M2 blockers have not been extensively used due to their side effects and the rapid development of resistant virus mutants (Magden J et al., Appl. Microbiol. Biotechnol. (2005) 66:612-621). In addition, rather unspecific viral drugs, such as ribavirin, can be used to treat influenza and other virus infections (Eriksson, B. et al., Antimicrob. Agents Chemother. (1977) 11:946-951) but Ribavirin has been approved only in a few countries due to its severe side effects (Furuta et al., Antimicrobial Agents and Chemotherapy (2005) 49(3):981-986). The Standard of Care has been Oseltamivir for years, despite its significant limitations; 1) a rather limited treatment window as it has to be administred within 48 h of the onset of symptoms; 2) a partial efficacy in high-risk and hospitalized patients and the failure to prevent complications in some patients; 3) the existence of resistance by many influenza strains, as reported by IRIS (http://apps.who.int/iris/handle/10665/205523); and 4) a low potency against flu B and the fact that Oseltamivir monotherapy has not prevented death in patients with severe pandemic H1N1 (Nukiwa et al., Clin Infect Dis (2010) 51(6):725-731), H5N1 (Chan et al., J lnfect Dis (2012) 206:1359-1366) or H7N9 (Hu et al., Lancet (2013) 381: 2271-2277). An obvious strategy to improve on the standard of care would be to combine drugs with different modes of action (“MOA”) or develop drugs with new MOAs that could be used as stand-alone.
It is an object of the present invention to identify such new compounds with new MOA which are effective against viral diseases, particularly influenza, and which have improved pharmacological properties.